Addressing data fragmentation and drug development barriers in primary mitochondrial diseases: the C-Path Primary Mitochondrial Diseases (PMD) Task Force approach to data harmonization, integration, and endpoint development

Background Primary mitochondrial diseases (PMD) have a minimum point prevalence of approximately 1 in 5000 births worldwide [1], although prevalence estimates may differ by region and population studied. Despite this significant prevalence and the identification of over 470 causative genes, most PMD still lack FDA-approved treatments, leaving patients dependent on supportive and off-label care. While recent approvals for Barth Syndrome and Thymidine Kinase 2 Deficiency (TK2d) represent important progress, nearly all other PMD remain without targeted therapies. In response to these challenges, the Critical Path Institute’s Primary Mitochondrial Diseases Task Force (PMD-TF), launched in January 2024, was established as an unprecedented collaborative effort to accelerate therapeutic development through data integration, standardization, and evidence-based endpoint development. This white paper outlines a strategic approach to overcoming key barriers in PMD drug development, including the recent failure of traditional outcome measures and the urgent need for disease-specific assessment tools. Recent regulatory successes further demonstrate that PMD drug development is feasible and have been enabled by improvements in trial design, a deeper understanding of genotype–phenotype relationships, and the integration of patient and caregiver perspectives. Building on this progress, patient and clinician-led registries have emerged as critical tools, supporting rapid enrollment and the collection of detailed, patient-centered real-world data. The PMD-TF’s preliminary work represents the first coordinated cross-registry harmonization effort in the PMD community, facilitating broader collaboration and data integration. Results Analysis of the current PMD landscape highlights ongoing challenges, including disease heterogeneity, limited patient enrollment, and the lack of sensitive, disease-specific endpoints, all of which have contributed to repeated clinical trial failures. Evaluation of existing registries shows areas of overlap and substantial misalignment in collected data elements, limiting cross-study comparability and large-scale analyses. In this context, PMD-TF efforts demonstrate the feasibility of cross-registry harmonization through alignment of data dictionaries and identification of shared and distinct domains. Conclusion Coordinated data harmonization and cross-sector collaboration are essential to advancing PMD drug development. Establishing common data standards and leveraging aggregated datasets will improve study design, inform regulatory decision-making, and accelerate the development of effective, patient-centered therapies that enhance outcomes and quality of life for individuals with PMDs. Clinical trial number Not applicable.